Apparatus and method for delivering a therapeutic agent to ocular tissue

ABSTRACT

A method is provided for delivering at least one therapeutic agent to an ocular tissue of a subject. The method includes providing an apparatus including at least one electrode, a medicament layer including at least one therapeutic agent, an electrical signal source, and logic configured to control the electrical signal source. The at least one electrode has oppositely disposed first and second dome-shaped major surfaces. The medicament layer is disposed on at least a portion of the second major surface. The electrical signal source is electrically connected to the at least one electrode. At least one portion of the first major surface is placed into contact with the ocular tissue so that the at least one portion substantially conforms to the contour of the ocular tissue. The electrical signal source provides a signal having certain characteristics to motivate the at least one therapeutic agent into the ocular tissue.

RELATED APPLICATIONS

This application claims priority from U.S. Provisional PatentApplication Ser. No. 61/100,464, filed Sep. 26, 2008, and is acontinuation-in-part of U.S. patent application Ser. No. 11/874,859,filed Oct. 18, 2007, which claims priority from U.S. Provisional PatentApplication Ser. No. 60/829,978, filed on Oct. 18, 2006 (now expired).The subject matter of the aforementioned applications is herebyincorporated by reference in their entireties.

TECHNICAL FIELD

The present invention relates generally to an apparatus and method fordelivering a therapeutic agent to ocular tissue, and more particularlyto a dielectrophoretic apparatus and related method for delivering atleast one therapeutic agent to an ocular tissue of a subject.

BACKGROUND OF THE INVENTION

The treatment of ocular diseases in mammals, including humans andnon-humans alike often requires that drugs or other agents be deliveredto the eye in a therapeutic dose. Such diseases may occur in thechoroid, the retina, the crystalline lens, and the optic nerve, as wellas other ocular structures. One treatment methodology is to deliver anocular agent to these structures via local drug administration, asopposed to systemic drug administration. This permits agents to bedelivered directly to a site requiring evaluation and/or therapy.Because of drug localization, there is less of a concern for release ordissemination of the drug beyond the site of delivery. Such is also thecase for other body sites where it is desirable to limit drugdissemination or systemic administration, yet still provide drugs invarious formulations.

In many instances, however, local drug administration to the eye is noteasily accomplished. Thus, localized drug administration often requiresrather invasive procedures to gain access to the various ocularstructures being treated. This may entail inserting a conduit, such as afine gauge needle into the eye, or forming an incision for positioningof a device, such as a drug depot. Consequently, such treatmenttypically requires a visit to a hospital or doctor's office wheretrained health care professionals can perform the necessary, relativelymore invasive procedures to achieve local drug administration.

Another form of localized drug delivery may be accomplished usingiontophoresis. Although iontophoresis is generally well-accepted bypatients and medical professionals, there are some risks involved. Forexample, high current intensity or long treatment times can lead topain, burning sensations, skin irritation, erythema, blister formation,and skin necrosis. In the most extreme cases, high currents produced bydirect current iontophoresis can short through a patient's heart.Iontophoresis also requires reformulated compounds for application and,thus, cannot typically use market-available drugs.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, an apparatus isprovided for delivering at least one therapeutic agent to an oculartissue of a subject. The apparatus comprises at least one electrode, amedicament layer including the at least one therapeutic agent, anelectrical signal source, and logic configured to control the electricalsignal source. The at least one electrode has oppositely disposed,dome-shaped first and second major surfaces. The first major surface iscurved such that the first major surface substantially conforms to thecontour of the ocular tissue when the first major surface is in contactwith the ocular tissue. The medicament layer is disposed on at least aportion of the second major surface. The electrical signal source is forproviding a signal having certain characteristics. The electrical signalsource is electrically connected to the at least one electrode. Thecertain characteristics of the electrical signal source comprise atleast one orienting frequency and at least one motivating frequencysufficient to motivate the at least one therapeutic agent into theocular tissue.

According to another aspect of the present invention, a system isprovided for delivering at least one therapeutic agent to an oculartissue of a subject. The system comprises an apparatus, an electricallead, and a displacement device. The apparatus comprises at least oneelectrode, a medicament layer, an electrical signal source, and logicconfigured to control the electrical signal source. The at least oneelectrode has oppositely disposed, dome-shaped first and second majorsurfaces. The first major surface is curved such that the first majorsurface substantially conforms to the contour of the ocular tissue whenthe first major surface is in contact with the ocular tissue. Themedicament layer is disposed on at least a portion of the second majorsurface. The electrical signal source is for providing a signal havingcertain characteristics. The electrical signal source is electricallyconnected to the at least one electrode. The certain characteristics ofthe electrical signal source comprise at least one orienting frequencyand at least one motivating frequency sufficient to motivate the atleast one therapeutic agent into the ocular tissue. The electrical leadincludes oppositely disposed proximal and distal ends. The proximal endis electrically connected to the electrical signal source and the distalend is electrically connected to the at least one electrode. Theelectrical lead is for delivering the electrical signal to the at leastone electrode. The displacement device is for facilitating applicationof the first major surface of the at least one electrode to the oculartissue. The displacement device is securely connected to the electricallead.

According to another aspect of the present invention, a method isprovided for delivering at least one therapeutic agent to an oculartissue of a subject. One step of the method includes providing anapparatus comprising at least one electrode, a medicament layerincluding the at least one therapeutic agent, an electrical signalsource, and logic configured to control the electrical signal source.The at least one electrode has oppositely disposed,electrically-conductive first and second dome-shaped major surfaces. Themedicament layer is disposed on at least a portion of the second majorsurface. The electrical signal source is electrically connected to theat least one electrode. Next, the electrical signal source is caused toprovide a signal having certain characteristics to motivate the at leastone therapeutic agent into the ocular tissue.

According to another aspect of the present invention, a method isprovided for delivering at least one therapeutic agent to an oculartissue of a subject. One step of the method includes providing anapparatus comprising at least one electrode, a medicament layerincluding the at least one therapeutic agent, an electrical signalsource, and logic configured to control the electrical signal source.The at least one electrode has oppositely disposed,electrically-conductive first and second dome-shaped major surfaces. Themedicament layer is disposed on at least a portion of the second majorsurface. The electrical signal source is electrically connected to theat least one electrode. Next, at least one of the medicament layer andthe at least one electrode is shaped so that delivery of the electricalsignal to the at least one electrode motivates the at least onetherapeutic agent into the select region of the subject's eye. Theelectrical signal source is then caused to provide an electrical signalto the at least one electrode to motivate the at least one therapeuticagent into the selection region of the subject's eye.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features of the present invention will becomeapparent to those skilled in the art to which the present inventionrelates upon reading the following description with reference to theaccompanying drawings, in which:

FIG. 1A is a perspective view showing an open configuration of anapparatus for delivering a drug to an ocular tissue constructed inaccordance with one aspect of the present invention;

FIG. 1B is a perspective view showing the apparatus of FIG. 1A in aclosed configuration;

FIG. 2 is a cross-sectional view of a human eye;

FIG. 3A is an exploded perspective view showing the apparatus in FIG.1A;

FIG. 3B is a different perspective view showing the apparatus in FIG.3A;

FIG. 4A is a cross-sectional view of the apparatus taken along Line4A-4A in FIG. 1A;

FIG. 4B is a cross-sectional view of the apparatus taken along Line4B-4B in FIG. 1B;

FIG. 5 is a process flow diagram illustrating a method for delivering adrug to an ocular tissue of subject according to another aspect of thepresent invention;

FIG. 6 is a perspective view showing a medicament layer being placedonto at least one electrode of the apparatus in FIG. 1A;

FIG. 7 is a perspective view showing the medicament layer disposed onthe at least one electrode in FIG. 6;

FIG. 8 is a perspective view showing a displacement device constructedin accordance with another aspect of the present invention;

FIG. 9 is a perspective view showing the apparatus in FIG. 1A placedover a human eye using the displacement device in FIG. 8;

FIG. 10 is a cross-sectional view taken along Line 10-10 in FIG. 9showing the apparatus of FIG. 9 placed over the human eye;

FIG. 11 is a cross-sectional view showing the apparatus in FIG. 10delivering a drug (arrows) to an anterior segment of the human eye;

FIG. 12 is a cross-sectional view showing the apparatus in FIG. 10delivering a drug (arrows) to a posterior segment of the human eye;

FIG. 13 is a graph comparing ionic conductivity of triamcinoloneacetonide (TA) through rabbit ocular tissue over time;

FIG. 14 is a calibration curve for TA. In FIG. 14, a 1 mL suspension ofTA was separated into 8 equal portions of approximately 0.13 mL (5.0 mgTA). The negative control contained no drug. The positive control wastaken from the standard concentration used in the calibration curve.Based on the 5.0 mg TA initial sample and the 3 mL B-Cell bottom chambercapacity, the maximum final concentration=1.67 mg/mL. Percent throughputwas calculated based on this maximum. Total percent throughput is basedon the entire 40 mg present in the vial—17.72 mg, or 44 percent of those40 mg were detected by UV-Vis;

FIG. 15A is a concentration curve for ranibizumab at 220 nm absorbance;

FIG. 15B is a concentration curve for ranibizumab at 278 nm absorbance;and

FIG. 16 is a graph showing DEA analysis of a water-based maculardegeneration drug (i.e., TIMP-3) in which the water-based drug solutionssamples exhibited UV-Vis activity different from that of pure water atwavelengths below 300 nm.

DETAILED DESCRIPTION

The present invention relates generally to an apparatus and method fordelivering at least one therapeutic agent to an ocular tissue, and moreparticularly to a dielectrophoretic apparatus and related method fordelivering at least one therapeutic agent to an ocular tissue of asubject. As representative of the present invention, FIGS. 1A-Billustrate an apparatus 10 for delivering at least one therapeutic agentto an ocular tissue of a subject. One aspect of the present inventionprovides a non-invasive apparatus 10 and method 12 (FIG. 5) that takesadvantage of the principles of dielectrophoresis to modulate delivery ofat least one therapeutic agent to ocular tissue. Unlike conventionaltherapeutic agent delivery modalities, one aspect of the presentinvention provides increased patient safety, the ability to deliver bothpolar and non-polar agents of varying size, programmable dose control,and potentially lower cost of subject care.

Unless otherwise defined, all technical terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich the present invention pertains.

In the context of the present invention, the term “ocular tissue” canrefer to any one or combination of the tissues comprising the eye, suchas the sclera, the conjunctiva, the cornea, the eyelid, tissues withinthe sclera (e.g., the retina) and outside the sclera (e.g., ocularmuscles within the orbit), and tissues neurologically connected to (butdistinct from) the eye, such as the optic nerve, the geniculate nucleus,and the visual cortex.

As used herein, the term “subject” can refer to any warm-bloodedorganism including, but not limited to, human beings, pigs, rats, mice,dogs, goats, sheep, horses, monkeys, apes, rabbits, cattle, etc.

As used herein, the terms “therapeutic agent”, “drug”, “agent”,“chemical compound”, and “chemical substance” can refer to any polar ornon-polar molecule or moiety that is capable of exhibiting a dipolemoment when exposed to an electric field. The terms can include, but arenot limited to, therapeutically effective agents (i.e., agents that arecapable of having a biological effect), such as pharmaceutical agents,drugs, or biological agents.

As used herein, the term “medicament layer” can refer to a suitablereservoir for storing and releasing at least one therapeutic agent,either with or without a vehicle.

As used herein, the term “vehicle” can refer to any non-toxic carriercomposition suitable for administration of a drug or agent into oculartissue. Examples of vehicles can include any of the standardpharmaceutical carriers, such as a phosphate buffered saline solution,water, emulsions (e.g., oil/water emulsions), various types of wettingagents, and excipients.

As used herein, the term “signal” can refer to voltage signals andcurrent signals.

As used herein, the term “logic” can refer to hardware, firmware,software and/or combinations thereof to perform a function(s) or anaction(s), and/or to cause a function or action from another component.For example, based on a desired application or need, logic may include asoftware controlled microprocessor, discreet logic, such as anapplication specific integrated circuit (ASIC), a programmed logicdevice, memory device containing instructions, or the like. “Logic” mayalso be fully embodied as software on a computer-readable medium.

As used herein, the term “therapeutically effective amount” can refer tothat amount of a therapeutic agent that results in amelioration ofsymptoms or a prolongation of survival in a subject with an oculardisease or condition. A therapeutically effective amount relieves tosome extent one or more symptoms of an ocular disease or condition orreturns to normal either partially or completely one or morephysiological or biochemical parameters associated with or causative ofthe ocular disease or condition.

As used herein, the term “anterior segment” can refer to refer to atleast one of the cornea, anterior chamber, iris, ciliary body, and lensof the eye.

As used herein, the term “posterior segment” can refer to at least oneof the vitreous, posterior chamber, choroid, retina, sclera, and opticnerve of the eye.

One aspect of the present invention includes an apparatus 10 (FIGS.1A-B) and method 12 (FIG. 5) for delivering at least one therapeuticagent to an ocular tissue of a subject via dielectrophoresis. To date,most devices and methods for delivering therapeutic agents (e.g., drugs)aided by an electromotive force have involved the use of a simplecathode or anode coupled with a drug source and a direct current (DC)electrical signal. The use of a DC electrical signal alone, however, mayhave certain disadvantages including, but not limited to, the formationof harmful or undesirable chemical byproducts at the cathode or anode.Moreover, such devices and methods are characterized as “iontophoresis”devices and methods since they are primarily limited to effectingtransport of ionic or strongly polar compounds. Many compounds(including drugs) may not be polar or ionic and/or may be difficult toionize, rendering the use of iontophoretic devices and methodsineffective on such compounds.

Regarding polarization, many compounds exhibit no dipole (areas of equalcharge separated by a distance) in the absence of an electric fieldbecause no free charges exist on any site of the compound or, ifpresent, the charges are randomly distributed such that no net chargeexists on the compound. Such compounds may be polarized and achieve anet dipole if they contain sites capable of being acted upon by anapplied electric field. Such sites may comprise any distinct chemicalgroup or moiety within a larger compound that is capable of beingattracted or repelled by an applied electric field. The sites are termed“nanosites” when their size is less than about 100 nanometers. Suchnanosites can include, for example, carbonyl, sulfoxide, nitro, andhydroxide groups.

Unlike iontophoresis, one aspect of the present invention includes adielectrophoretic apparatus 10 (FIGS. 1A-B) and method 12 (FIG. 5) formotivating any polarizable chemical compound, including compounds thatare difficult to polarize, such as non-polar drugs and large moleculecompositions. Dielectrophoresis involves providing a non-uniformalternating (AC) or DC electric field to a compound or agent. Thenon-uniform electric field, in addition to inducing a dipole in thecompound or agent, sets up an electrical field gradient that provides anelectromotive force on the newly polarized compound or agent, themagnitude and direction of which are dependent on several factors. Amore detailed explanation of dielectrophoresis and its operatingprinciples are disclosed in U.S. patent application Ser. No. 11/874,859(hereinafter, “the '859 application”), the entirety of which is herebyincorporated by reference.

One aspect of the present invention includes an apparatus 10 (FIGS.1A-B) and method 12 (FIG. 5) for delivering at least one therapeuticagent to an ocular tissue of a subject, such as a human eye 20 (FIG. 2).As shown in FIG. 2, about one-sixth of the outer layer of the eye 20bulges forward as the cornea 22. The cornea 22 is the primary structurefocusing light entering the eye 20 (along with the secondary focusingstructure, the lens 24). Along its circumference, the cornea 22 iscontinuous with the sclera 26, which is the white, opaque portion of theeye 20. The sclera 26 provides protection and serves as an attachmentfor the extraocular muscles (not shown) that move the eye 20. The eye 20additionally includes the conjunctiva 28, which begins at the outer edgeof the cornea 22 and covers the visible part of the sclera 26. Theconjunctiva 28 secretes oils and mucous that moisten and lubricate theeye 20. Other portions of the eye 20 include the anterior compartment30, the posterior compartment 32, the iris 34, the optic nerve 36, themacula lutea 38, the retina 40, the choroid 42, and the pars plana 43.

In one aspect of the present invention, the apparatus 10 (FIGS. 1A-B)comprises at least one electrode 44, a medicament layer 46 including atleast one therapeutic agent, an electrical signal source 48 (FIG. 10),and logic configured to control the electrical signal source. The atleast one electrode 44 (FIGS. 1A-B) can comprise any one or combinationof electrodes capable of providing an electric field to an areasufficient to motivate at least one therapeutic agent into an oculartissue. To ensure proper transmission of electrical energy, the at leastone electrode 44 includes at least two separate, electrically-conductiveportions or components that are biased against one another. The at leastone electrode 44 can comprise a single electrode or, alternatively, twoor more independent, electrically-conductive members separated by aninsulator. For example, the at least one electrode 44 can comprise anyirregularly-shaped or non-uniform electrode capable of providing anon-uniform electric field to an area sufficient to inducedielectrophoretic transport of at least one therapeutic agent.

The at least one electrode 44 has a flexible, dome-shaped configurationthat is contoured to the three-dimensional shape of the ocular tissue(e.g., the eye 20). The at least one electrode 44 includes anelectrically-conductive first major surface 50 oppositely disposed froman electrically-conductive second major surface 52 (FIGS. 4A-B). Thefirst major surface 50 is curved such that the first major surfacesubstantially conforms to the contour of the ocular tissue when thefirst major surface is in contact with the ocular tissue. For example,the first major surface 50 can have a radius of curvature substantiallysimilar to the radius of curvature of the sclera 26 or cornea 22. Asdescribed in more detail below, the at least one electrode 44 can bejudiciously shaped to facilitate delivery of at least one therapeuticagent to a select region of ocular tissue.

The at least one electrode 44 can be made of any material capable ofconducting an electrical current, such as platinum, platinum-iridium,stainless steel, gold-plated copper, or the like. Additionally oroptionally, at least a portion of the at least one electrode 44 isembedded within a polymeric material (or other similar material) (e.g.,silicone) to protect ocular tissue from abrasion, promotebiocompatibility and/or electrical conduction, and facilitate fixing theat least one electrode in place during delivery.

As one example of the present invention, it will be appreciated thatongoing reference to the at least one electrode 44 shall include aninterdigitated electrode. In general, an interdigitated electrode caninclude any set of at least two electrodes that contain interwovenprojections. As shown in FIGS. 3A-B, the at least one electrode 44(e.g., an interdigitated electrode) is comprised of a firstelectrically-conductive member 128 that is separated by an insulatorfrom a second electrically-conductive member 130. Each of the first andsecond electrically-conductive members 128 and 130 comprise a “comb”electrode (i.e., an electrode having a number of relatively long, flatprongs that are evenly spaced) whose prongs are interleaved with oneanother. The at least one electrode 44 (e.g., an interdigitatedelectrode) can additionally include at least one passage 54 sufficientto allow at least one therapeutic agent to pass therethrough. The atleast one electrode 44 (e.g., an interdigitated electrode) can have amaterial composition and dimensions that allow for substantialflexibility and conformability to ocular tissue. As noted above, thefirst and second electrically-conductive members 128 and 130 comprisingthe at least one electrode 44 (e.g., an interdigitated electrode) may bespaced apart by an insulator (not shown) made of any insulating materialsuitable for use in designing an arrangement of electrodes and/orcircuits (e.g., fiberglass or TEFLON). More specific details concerningthe design and function of interdigitated electrodes are disclosed inthe '859 application.

As shown in FIG. 1A, the medicament layer 46 is disposed on at least aportion the second major surface 52 (FIGS. 3A-B) of the at least oneelectrode 44 (e.g., an interdigitated electrode). The medicament layer46 can be shaped to preferentially deliver the at least one therapeuticagent to a select region of ocular tissue. The ring-shaped medicamentlayer 46 shown in FIGS. 3A-B, for example, can facilitate selectivedelivery of at least one therapeutic agent to the sclera 26 of the eye20 while also avoiding or mitigating delivery of the at least onetherapeutic agent to the cornea 22. It will thus be appreciated that themedicament layer 46 can have any size and shape, depending upon theparticular application of the present invention.

The medicament layer 46 can comprise a matrix formed from a sponge, gel(e.g., hydro-gel), viscous liquid, or the like. The medicament layer 46can be applied to the second major surface 52 of the at least oneelectrode 44 (e.g., an interdigitated electrode) by spraying, coating orplacing. The material(s) used to form the medicament layer 46 caninclude any one or combination of materials capable of storing andreleasing the at least one therapeutic agent and, optionally, at leastone vehicle. For example, the medicament layer 46 can be comprised of abiocompatible, non-biodegradable polymeric material made from ahomopolymer, a copolymer, straight polymers, branched polymers,cross-linked polymers, stimuli-responsive polymers, or a combinationthereof. Examples of such polymers can include silicone, polyvinylalcohol, ethylene vinyl acetate, polylactic acid, nylon, polypropylene,polycarbonate, cellulose, cellulose acetate, polyglycolic acid,polylactic-glycolic acid, cellulose esters, polyethersulfone, acrylics,their derivatives, and combinations thereof. It should be appreciatedthat the medicament layer 46 may also be disposed on the first majorsurface 50 of the at least one electrode 44 (e.g., an interdigitatedelectrode) or at least partially embedded therein.

The medicament layer 46 can include any one or combination of polarand/or non-polar therapeutic agents. For example, the medicament layer46 can include such ophthalmic medications as anti-infectives,antibiotics, anti-inflammatory agents (e.g., triamcinolone),non-steroidal anti-inflammatory agents, anti-fungal agents, glaucomamedications (e.g., alpha-2 agonists, beta blockers, carbonic anhydraseinhibitors, miotics, prostaglandin agonists, and sympathomimetics), mastcell stabilizers, anti-proliferative agents, steroids, corticosteroids,hormones, small molecules, cytokines, growth factors, antibodies orantibody fragments, immune system modulators, vectors, polynucleotides,nucleic acids, RNAs, miRNAs, siRNAs, DNAs, aptamers, carbohydrates,recombinant or native peptides, polypeptides and proteins (e.g.,TIMP-3), enzymes, enzyme inhibitors, and combinations thereof. Morespecific examples of such therapeutic agents, as well as others areknown in the art.

It will be appreciated that the apparatus 10 can include more than onemedicament layer 46, and that each medicament layer can contain the sameor different type of therapeutic agent. Additionally, it will beappreciated that a single medicament layer 46 can include two or morecompartments (not shown), each of which is also made from a gel, viscousliquid, etc. If appropriate, mixtures of therapeutic agents can bestored in a common compartment while other single therapeutic agents (ormixtures) are stored in one or more separate compartments. The releasecharacteristics of the respective compartments can be adjusted accordingto specific applications of the present invention.

The apparatus 10 additionally comprises an electrical signal source 48(FIG. 10) for providing an electrical signal to the at least oneelectrode 44 (e.g., an interdigitated electrode). The electrical signalsource 48 is capable of providing an AC signal, a DC signal, or acombination thereof. The electrical signal source 48 can be electricallyconnected to the at least one electrode 44 (e.g., an interdigitatedelectrode) via a direct electrical link or a wireless link (e.g., an RFlink). As shown in FIG. 10, for example, proximal and distal ends 56 and58 of an electrical lead 90 can be electrically connected to theelectrical signal source 48 and the at least one electrode 44 (e.g., aninterdigitated electrode), respectively.

In one example of the present invention, the electrical signal source 48provides an electrical signal having certain characteristics. Thecertain characteristics can comprise at least one orienting frequency toorient the at least one therapeutic agent, and at least one motivatingfrequency sufficient to motivate the at least one therapeutic agent intothe ocular tissue. For example, the at least one orienting frequency cancomprise an AC signal having a relatively low frequency, and themotivating frequency can comprise an AC signal having a relatively highfrequency. Alternatively, the at least one orienting frequency cancomprise an AC signal delivered from an AC signal source, and the atleast one motivating frequency can comprise a DC signal delivered from aDC signal source. Other examples of electrical signals having certaincharacteristics are disclosed in the '859 application and describedbelow.

The apparatus 10 additionally includes logic configured to control theelectrical signal source 48. The logic may be configured to monitor andrecord current and phase data from the at least one electrode 44 (e.g.,an interdigitated electrode) and to calculate dielectric informationregarding the at least one therapeutic agent as a function of theelectrical signal frequency. Dielectric information may include, but isnot limited to, capacitance, conductance, permittivity (ε′), dielectricloss factor (ε″), and impedance information. Dielectric information maybe plotted or stored as a function of electrical signal frequency tofacilitate selection of appropriate operating frequencies that allow forthe at least one therapeutic agent to be motivated into ocular tissue.More specific details concerning the logic used to modulate theelectrical signal are disclosed in the '859 application.

Referring to FIGS. 3A-B, the apparatus 10 also includes a positioningmember 62 for placing at least a portion of the first major surface 50of the at least one electrode 44 (e.g., an interdigitated electrode)into contact with an ocular tissue. The positioning member 62 can beattached to the at least one electrode 44 (e.g., an interdigitatedelectrode) at one or more points and/or at least partially envelop theat least one electrode 44 (e.g., an interdigitated electrode). Moreover,the positioning member 62 can have any desired shape and size sufficientto facilitate placement of the at least one electrode 44 (e.g., aninterdigitated electrode). The positioning member 62 can be made of anelectrically-insulative material (e.g., plastic, silicone, etc.), andcan have a rigid, semi-rigid, or flexible configuration.

In one example of the present invention, the positioning member 62 cancomprise a clam-shaped housing 64. As shown in FIGS. 3A-B, the housing64 comprises a first opposable member 66, a second opposable member 68,a hinge mechanism 70 that operably connects the first and secondopposable members, and a securing mechanism 72 for mating the first andsecond opposable members. The housing 64 can have a rigid or semi-rigidconfiguration. Additionally, all or only a portion of the housing 64 canbe made from an electrically-insulative material, such as silicone orhardened plastic.

As shown in FIGS. 3A-B, the first opposable member 66 is ring-shaped andincludes oppositely disposed first and second end portions 74 and 76.The first opposable member 66 includes a central opening 78 that extendsbetween an upper surface 80 and a lower surface 82. The central opening78 is adapted to receive the at least one electrode 44 (e.g., aninterdigitated electrode). The at least one electrode 44 (e.g., aninterdigitated electrode) can be securely seated within the centralopening 78 of the first opposable member 66 using an adhesive or,alternatively, by integrating the periphery of the first major surface50 into an inner surface 84 of the first opposable member. It will beappreciated that other means can be used to securely seat the at leastone electrode 44 (e.g., an interdigitated electrode) in the centralopening 78. For example, the inner surface 84 of the first opposablemember 66 can include a ridge or ledge (not shown) upon which theperiphery of the first major surface 50 can be securely seated.

The second opposable member 68 has a configuration similar to theconfiguration of the first opposable member 66. As shown in FIGS. 3A-B,for example, the second opposable member 68 is ring-shaped and includesoppositely disposed first and second end portions 74 and 76. The secondopposable member 68 also includes a central opening 78 that extendsbetween an upper surface 80 and a lower surface 82. A dome-shaped member86 is securely seated within the central opening 78 of the secondopposable member 68. The dome-shaped member 86 is configured to coverthe second major surface 52 of the at least one electrode 44 (e.g., aninterdigitated electrode) and the medicament layer 46 when the first andsecond opposable members 66 and 68 are securely mated together. Thedome-shaped member 86 can be made of a rigid or semi-rigid material(e.g., a hardened plastic), and can be secured within the centralopening 78 of the second opposable member 68 using an adhesive, forexample, or any other suitable means. It should be appreciated that thedome-shaped member 86 can be a continuous, integral part of the secondopposable member 68.

The hinge mechanism 70 of the housing 64 provides a means forselectively mating the first and second opposable members 66 and 68. Asshown in FIGS. 3A-B, the hinge mechanism 70 is integrally formed withthe second end portion 76 of each of the first and second opposablemembers 66 and 68. The hinge mechanism 70 can have a known hingeconfiguration, such as a strap hinge, butt hinge, or back flap hinge. Asshown in FIGS. 3A-B, for example, the hinge mechanism 70 can comprise afemale portion 88 integrally formed with the second end portion 76 ofthe first opposable member 66, and a male portion 90 integrally formedwith the second end portion of the second opposable member 68. It willbe appreciated that the hinge mechanism 70 can have a configurationother than the one shown in FIGS. 3A-B. For example, the hinge mechanism70 can have a one-piece configuration (not shown) comprising a singlepiece of material (e.g., a U-shaped piece of flexible plastic) thatflexibly connects the second end portion 76 of the first opposablemember 66 with the second end portion of the second opposable member 68.

The housing 64 additionally comprises a securing mechanism 72 for matingthe first opposable member 66 with the second opposable member 68. Thesecuring mechanism 72 comprises a male member 92 integrally formed withthe first end portion 74 of the first opposable member 66, and femalemember 94 integrally formed with the first end portion of the secondopposable member 68. The male member 92 comprises a base portion 96 thatis securely mated with an insertion tab 98. The female member 94comprises tab-shaped member mating with the base portion 96 of the malemember 92. It will be appreciated that the securing mechanism 72 can belocated elsewhere about the housing 64, and that the securing mechanismcan have a configuration other than the one shown in FIGS. 3A-B.

FIG. 5 is a process flow diagram illustrating another aspect of thepresent invention. In FIG. 5, a method 12 is provided for delivering atleast one therapeutic agent to an ocular tissue of a subject. The method12 includes providing an apparatus 10 at Step 14. The apparatus 10 canbe identically or similarly constructed as the apparatus shown in FIGS.1A-B. For example, the apparatus 10 can comprise at least one electrode44 (e.g., an interdigitated electrode), a medicament layer 46 includingat least one therapeutic agent, an electrical signal source 48, andlogic configured to control the electrical signal source.

At Step 16, at least a portion of the apparatus 10 is placed intocontact with the ocular tissue of the subject. The placement location,type of therapeutic agent (or agents) comprising the medicament layer46, and the size and shape of the medicament layer will depend on thesubject's anatomy, the age of the subject, the presence or absence of anocular condition or disease, as well as other factors. To treat retinalinflammation, for example, the medicament layer 46 can include a desiredconcentration of triamcinolone. Alternatively, in a subject withadvanced macular degeneration, the medicament layer 46 can include adesired concentration of ranibizumab or TIMP-3.

Prior to contacting the apparatus 10 with the ocular tissue, themedicament layer 46 can be shaped to optimize delivery of thetherapeutic agent(s) to the ocular tissue. In a subject suffering fromposterior segment eye disease, for example, the medicament layer 46 canbe shaped as shown in FIGS. 3A-B to optimize delivery of the therapeuticagent(s) through the pars plana 43 and into at least one tissuecomprising the posterior segment of the eye 20. Alternatively, in asubject suffering from corneal inflammation, the medicament layer 46 canhave a circular or oval-shaped configuration (FIG. 11) and be placed onor near the center of the at least one electrode 44 (e.g., aninterdigitated electrode) adjacent the corneal surface 14 to facilitatedelivery of the therapeutic agent(s) into the inflamed corneal tissue.

If it has not been done so already, the medicament layer 46 is placedinto contact with the second major surface 52 of the at least oneelectrode 44 (e.g., an interdigitated electrode) (FIGS. 6-7) by firstdepressing the insertion tab 98 of the securing mechanism 72 so that thethe second opposable member 68 is freed from the first opposable member66. Next, the first and second opposable members 66 and 68 are separated(e.g., pulled apart using tactile force) so that the housing 64 obtainsan opened configuration (FIG. 6). In the opened configuration, themedicament layer 46 can be placed into contact with the second majorsurface 52 of the at least one electrode 44 (e.g., an interdigitatedelectrode) (FIG. 7). After the medicament layer 46 is securely disposedon the second major surface 52, the second opposable member 68 is urgedtoward the first opposable member 66 (e.g., using tactile force) untilthe insertion tab 98 is received by the channel and the first and secondopposable members are securely mated with one another.

Next, a displacement device 100 (FIG. 8) is used to place the apparatus10 into contact with the ocular tissue. As shown in FIG. 8, thedisplacement device 100 comprises a lid speculum having oppositelydisposed first and second arm members 102 and 104. Each of the first andsecond arm members 102 and 104 has a flexible, wire-like configurationand includes proximal and distal end portions 106 and 108. The first andsecond arm members 102 and 104 can be separate segments or,alternatively, be integrally formed with one another (e.g., at theproximal end portion) in a U-shaped configuration. The first and secondarm members 102 and 104 can be made from any one or combination ofbiocompatible materials, such as titanium, stainless steel, or hardenedplastic.

The distal end portion 108 of each of the first and second arm members102 and 104 includes a channel 110 for receiving at least a portion ofan upper eyelid 112 and a lower eyelid 114 (respectively). Each of thechannels 110 is comprised of oppositely disposed first and second majorsegments 116 and 118 joined together by annular-shaped first and secondminor segments 120 and 122. It will be appreciated that each of thechannels 110 can have a configuration other than the one shown in FIG.8. For example, each of the channels 110 can be formed from asemi-cylindrical piece of solid material (e.g., plastic).

The displacement device 100 further comprises a connection member 124that operably joins the first and second arm members 102 and 104, aswell as the electrical lead 60. The connecting member 124 can have awedge-shaped configuration and be comprised of rigid or semi-rigidmaterial, such as rubber. The connecting member 124 includes a firstchannel (not shown in detail) for receiving the first and second armmembers 102 and 104, and a second channel 126 for receiving theelectrical lead 60. It will be appreciated that the connecting member124 can have any other configuration suitable for joining the first andsecond arm members 102 and 104 and the electrical lead 60.

If it has not been done so already, the electrical signal source 48 cannext be electrically connected to the at least one electrode 44 (e.g.,an interdigitated electrode) (FIG. 10). After doing so, the displacementdevice 100 is positioned substantially adjacent the eye 20. As thedisplacement device 100 is moved into position over the eye 20, thefirst and second arm members 102 and 104 can be moved towards oneanother using tactile force. The distal end portion 108 of each of thefirst and second arm members 102 and 104 can then be positioned aboutthe upper and lower eyelids 112 and 114 so that the channel 110 of eachof the first and second arm members engages at least a portion of theupper and lower eyelids (respectively). As shown in FIG. 9, the firstand second arm members 102 and 104 can then be released so that theupper and lower eyelids 112 and 114 are displaced and the surface of thesubject's eye 20 is exposed.

After displacing the upper and lower eyelids 112 and 114, the apparatus10 is positioned adjacent the subject's eye 20 so that the curvature ofthe first major surface 50 substantially conforms to the contour of theeye's surface (FIG. 10). It will be appreciated that the curvature ofthe first major surface 50 and the curvature of the subject's eye 20 canbe determined prior to placing the apparatus 10 to ensure a snug fitbetween the first major surface and the eye's surface. Additionally, itwill be appreciated that the apparatus 10 can be placed at otherpositions (e.g., over the subject's eyelids 112 and 114) to deliver thetherapeutic agent(s) to the ocular tissue.

At Step 18, the at least one therapeutic agent is motivated or deliveredinto the ocular tissue by causing the electrical signal source 48 toprovide an electrical to the at least one electrode 44 (e.g., aninterdigitated electrode). In one example of the method 12, theelectrical signal source 48 can be activated to send an AC signal havingcertain characteristics to the at least one 44 (e.g., an interdigitatedelectrode). The electrical signal source 48 can be activated to cyclethrough at least one decade of frequencies ranging from about 0.1 Hz toabout 20,000 Hz. For example, an AC signal can have an orientingfrequency of about 0.1 Hz to about 100 Hz, a motivating frequency ofbetween about 100 Hz and about 20,000 Hz, and an amplitude of betweenabout 1 V to about 10 V. Additionally, an AC signal can be applied forbetween about 1 minute and about 30 minutes. A more specific descriptionof the electrical signal and the logic used to modulate the electricalsignal is disclosed in the '859 application.

Application of the electrical signal motivates the at least onetherapeutic agent into the ocular tissue. As shown in FIGS. 11-12, forexample, application of an AC signal to the at least one electrode 44(e.g., an interdigitated electrode) provides a non-uniform electricfield, thereby inducing a dipole on the at least one therapeuticagent(s). This, in turn, sets up an electrical field gradient thatprovides an electromotive force on the newly polarized agent(s) to drivethe agent(s) into the subject's eye 20. By modifying the electricalsignal (i.e., the frequency, voltage, and time of application), thelogic, the apparatus 10 (e.g., the at least one electrode 44 or themedicament layer 46), or a combination thereof, the therapeutic agent(s)can be selectively delivered to a desired portion of the ocular tissue,e.g., an anterior compartment 30 (FIG. 11) or a posterior compartment 32(FIG. 12) of the subject's eye 20.

It will be appreciated that the method 12 of the present invention canbe used to deliver a therapeutically effective amount of the at leastone therapeutic agent to ocular tissue and thereby treat a variety ofocular diseases or conditions. Examples of ocular conditions or diseasesthat may be treated according to the method can include, but are notlimited to, macular edema, age-related macular degeneration, anterior,intermediate and posterior uveitis, HSV retinitis, diabetic retinopathy,bacterial, fungal or viral endophthalmitis, eye cancers, glioblastomas,glaucoma, glaucomatous degradation of the optic nerve, and combinationsthereof.

The present invention is further illustrated by the following examples,which are not intended to limit the scope of potential applications ofthe present invention.

EXAMPLE 1 Background

Nanodielectrophoresis is a method of drug delivery that uses AC todeliver drugs to target tissues. It offers several advantages overimplant devices and intravitreal injections, such as increased patientsafety, the ability to deliver both small and large compounds,programmable dose control, and potentially lower cost of care. Two invitro models of drug delivery were used for validity studies.Ranibizumab (48 kd) and triamcinolone acetonide (435 kd) were used forall studies.

Methods

Full thickness rabbit tissue (conjunctiva to retina) was mounted on thesurface of an inter-digitated electrode. The test compound(triamcinolone) was placed on the surface of the tissue and the ACelectrical field was activated. One millivolt of electricity was appliedat various frequencies (Table 1).

An inter-digitated electrode was placed on a full thickness rabbittissue section (conjunctiva to retina). The test compounds(triamcinolone and ranibizumab) were placed on the surface of the tissueand the AC electrical field was activated. 3 cc of medium was placedunderneath the tissue to simulate vitreous. Various frequencies,voltages, and time periods were tested (Table 1). The solution below thetissue was sampled for analysis.

Results

Studies using triamcinolone yielded concentrations ranging from0.280-0.970 mg/ml depending on the voltage, frequency, and time applied.The clinical dose of triamcinolone is 0.975 mg/ml (4 mg/4 mlvitreous+0.1 cc injection). In as little as 6.7 minutes, clinicallyefficacious doses could be reached in the preclinical system (FIG. 13).

Studies using ranibizumab, yielded concentrations of 0.070-0.171 mg/mldepending on the voltage, frequency, and time applied. The clinical doseof ranibizumab is 0.123 mg/ml (0.5 mg/4 ml vitreous+0.05 cc injection).In as little as 6.7 minutes, 92.8% throughput could be achieved (FIG.13).

TABLE 1 Experimental Results Concen- tration % Absorbance Low High (mg/Through- at Voltage Freq. Freq. Time Study mL) put 250 nm (mV) (Hz) (Hz)(min) Experimental Results of Kenalog in B-cell 1 0.996 59.6 3.84 4 101000 15 2 0.639 38.3 2.48 1 10 1000 15 3 0.846 50.7 3.27 1 100 1000 6.74 0.280 16.8 1.12 4 10 1000 6.7 5 0.796 47.7 3.08 1 10 1000 6.7 6 0.97058.1 3.74 1 100 1000 15 7 0.792 47.4 3.06 4 100 1000 15 8 0.587 35.22.29 4 100 1000 6.7 Experimental Results of Lucentis in B-cell 1 0.07042.1 0.719 4 10 1000 15 2 0.123 73.7 1.259 1 10 1000 15 3 0.155 92.81.585 1 100 1000 6.7 4 0.113 67.8 1.158 4 10 1000 6.7 5 0.168 100.81.721 1 10 1000 6.7 6 0.139 83.6 1.427 1 100 1000 15 7 0.129 77.1 1.3174 100 1000 15 8 0.171 102.5 1.750 4 100 1000 6.7 Pos. 0.129 77.1 1.317 4100 1000 15 Cont. Neg. No — — 4 100 1000 15 Cont. peaks

EXAMPLE 2 Concentration Calibration for Triamcinolone Acetonide

FIG. 14 illustrates the concentration calibration curve for experimentsinvolving triamcinolone acetonide. Tables 2 and 3 illustrate theparticular experimental parameters. Table 4 illustrates correlations ofconcentrations and different parameters.

TABLE 2 Concentration Concentration Wavelength Absorbance (mg/mLsuspension) (mg/mL TA) C0 238.9 0.519 1 0.375 240 0.212 C1 237.1 0.1620.8 0.3 C2 238 0.138 0.6 0.225 C3 238.9 0.131 0.4 0.15 240 0.09 C4 2350.087 0.2 0.075 243 0.084

TABLE 3 Concentration vs. Absorbance 1 0.212 0.375 0.8 0.162 0.3 0.60.138 0.225 0.4 0.1105 0.15 0.2 0.0855 0.075

TABLE 4 Parameter Correlation Voltage −0.34212 Frequency 0.277 Time0.5083

EXAMPLE 3 Lucentis Drug Transport

Lucentis was found to have two UV-Vis absorbance peaks, one at 278 nm(±10 nm) and one at 220 nm (±10 nm). Calibration curves and samplereadings were generated for both peaks and 220 nm yielded the bestcalibration curve and sample reads. For that reason, 200 nm is used asthe primary peak. All standards and samples were read 3×3 (3 scans of 3separate aliquots) (Table 5); all data presented is based on averages ofthe nine readings (FIGS. 15A-B).

TABLE 5 Standard Concentrations of Lucentis in HBSS ConcentrationAbsorbance Absorbance Standard (mg/mL) at 278 nm at 220 nm C0 0.1250.301 1.273 C1 0.100 0.219 1.025 C2 0.0625 0.068 0.654

Eight studies plus a positive and negative control were run in theB-cell (Table 1). For each of the 8 studies, 0.05 mL Lucentis (0.5 mg)was placed in the top chamber for transport through the tissue. Thebottom well of the B-cell contains 3 mL HBSS, so the maximum finalconcentration of drug delivered equals 0.5 mg/3 mL=0.1667 mg/mL. Table 1lists the concentration and the percent throughout (out of a maximum0.1667). The positive control was a 0.1667 mg/mL solution placeddirectly in the bottom B-cell chamber.

Percent throughput varied from a low outlier of 42 percent for the firststudy to 100 percent for studies 5 and 6. These 100 percent measurementscome in at 100.8 and 102.5, suggesting that there is a margin of erroraround 2.5 to 3 percent. It is also possible that measurements slightlyhigher than 100 percent could result from traces of additional Lucentisremaining in the B-cell from previous studies.

Statistical analysis showed weak correlations between the parameters andconcentrations, with negative correlations for Voltage and Time and apositive correlation for Frequency (Table 6).

TABLE 6 Correlations of Concentrations and Parameters ParameterCorrelation Voltage −0.3011 Frequency 0.404 Time −0.5636

In general, it appears that applying the AC electrical field within therange of times, frequencies, and voltages are effectively transportingthe drug through the tissue.

EXAMPLE 4

A DEA analysis of a macular degeneration drug, i.e., tissue inhibitor ofmetalloproteinases-3 (TIMP-3) was tested drug through shedded snake skinat 37° C. for 60 minutes. An interdigitated DEA electrode electrode wasrinsed with deionized water and the resulting solution analyzed byUV-Vis spectroscopy to determine whether any of the drug passed throughthe snake skin to reach the electrode. We were able to identify thecritical frequencies and noted that conductivity is very high (e.g.,10⁴), indicating that the drug moves quickly (FIG. 16). Because the drugis a water-based solution, we also ran the same volume of pure water onthe snake skin under the same conditions to rule out the possibilitythat the electrical behavior was due to the water. As shown in FIG. 16,the profile of the pure water sample is radically different from that ofthe drug and does not show breaks in conductivity at criticalfrequencies. Successful delivery of the drug through snake skin in theDEA has proven to be a good predictor of successful drug transport usingthe interdigitated electrodes.

From the above description of the invention, those skilled in the artwill perceive improvements, changes and modifications. Suchimprovements, changes, and modifications are within the skill of the artand are intended to be covered by the appended claims.

1-11. (canceled)
 12. A method for delivering at least one therapeuticagent to an ocular tissue of a subject, said method comprising the stepsof: providing an apparatus comprising at least one electrode, amedicament layer including the at least one therapeutic agent, anelectrical signal source, and logic configured to control the electricalsignal source, the at least one electrode having oppositely disposedfirst and second dome-shaped major surfaces, the medicament layer beingdisposed on at least a portion of the second major surface, theelectrical signal source being electrically connected to the at leastone electrode; placing at least one portion of the first major surfaceinto contact with the ocular tissue so that the at least one portionsubstantially conforms to the contour of the ocular tissue; and causingthe electrical signal source to provide a signal having certaincharacteristics to motivate the at least one therapeutic agent into theocular tissue.
 13. The method of claim 12, wherein said step of causingthe electrical signal source to provide a signal further comprises thesteps of: selecting at least one orienting frequency; and selecting atleast one motivating frequency.
 14. The method of claim 13, wherein eachof the at least one orienting frequency and the at least one motivatingfrequency comprises an alternating current (AC) signal.
 15. The methodof claim 13, wherein the at least one orienting frequency comprises anAC signal and the at least one motivating frequency comprises a directcurrent (DC) signal.
 16. The method of claim 12, wherein said step ofplacing at least a portion of the first major surface into contact withthe ocular tissue further comprises the steps of: providing adisplacement device that is operably joined with an electrical lead viaa connection member, the displacement device comprising oppositelydisposed, flexible first and second arm members, each of the arm membersincluding a distal end portion and a proximal end portion, the distalend portion of each of the first and second arm members respectivelyincluding first and second channels; positioning the displacement deviceabout the eye of the subject so that at least a portion of the upper andlower eyelids is disposed within the first and second channels of thedisplacement device, respectively; and operating the displacement deviceto sufficiently spread apart the upper and lower eyelids so that thefirst major surface of the at least one electrode contacts the oculartissue.
 17. The method of claim 12, wherein said step of placing atleast a portion of the first major surface into contact with the oculartissue further comprises the step of positioning the first major surfacesubstantially adjacent an ocular tissue selected from the groupconsisting of the sclera, the eyelid, and the cornea.
 18. The method ofclaim 12, wherein said step of placing at least a portion of the firstmajor surface into contact with the ocular tissue further comprises thestep of positioning the first major surface substantially adjacent orunder the conjunctiva. 19-23. (canceled)